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Moroccan Journal Of Public Health Vol. 1, N° 1 (2020), 105-114 ISSN: 2658-8099 Review

COVID-19: An Overview of Current progress and prospects in the frantic race to develop upcoming safe and effective SARS-CoV-2 Candidates

Lahcen WAKRIM, Mohammed Timinouni, Salsabil HAMDI.

Instiutt Pasteur du Maroc, Casablanca, Morocco *Corresponding Author E-mail: Lahcen WAKRIM

Article info SUMMARY Received October 2020 Accepted December 2020 Online December2020 Coronavirus disease 2019 (COVID-19) is an emerging infectious disease

caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). It keywords : Sars-cov2, Vaccine quickly spread around the world after its first emergence in Wuhan in Canidates, December 2019 to become a global pandemic with millions of

worldwide. As of 1 November 2020, nearly 46 million cases have been reported

globally and 1.2 million patients succumbed to the viral disease. Due to the lack of efficient and specific therapeutic and prophylactic options available and the need to contain the epidemic, and its economic, political, cultural, demographic and societal consequences, there is a strong consensus globally only the development of a safe and effective vaccine against COVID-19 is the best way to control and ultimately end the pandemic. Faced with the urgency imposed by the speed of expansion of covid-19, scientists are led to launch themselves into a race against the clock to produce a safe and effective coronavirus vaccine by next year. Once the vaccine has been developed, strong international coordination and cooperation between all stakeholders in the vaccine production process will be needed to ensure equitable availability of the vaccine to the global population.

(Lam et al. 2020). The etiological agent of COVID-19 has Introduction been confirmed on 7 January 2020 as a novel severe acute respiratory syndrome coronavirus 2 which is originally On March 11, 2020, the World Health Organization hosted by bats and might have been transmitted from declared the Coronavirus disease 2019 (COVID-19) zoonotic coronaviruses to humans by means of pangolin outbreak as a pandemic (Wu et al. 2020). COVID-19 was (Lam et al. 2020, WHO 2020) or other wild animals before firstly reported in Wuhan city, the capital of Hubei, China

105 Moroccan Journal Of Public Health Vol. 1, N° 1 (2020), 105-114 subsequently spread by means of human-to-human protein subunits, 9 non-replicating viral vectors, 7 transmission within a few months after the first case (Lu et inactivated viruses, 7 DNA , 7 RNAs, 3 replicating al. 2020, Zhang et al. 2020). In a preliminary report, viral vectors and 1 live attenuated virus (WHO 2020b). complete viral genome analysis revealed that the virus Although COVID-19 is caused by a new coronavirus, shared 88% sequence identity to two bat-derived SARS- previous research on other coronavirus vaccines, such as like coronaviruses, but more distant from SARS Feline-CoVs, MERS-CoV, SARS-CoV has provided coronavirus (Zhou et al. 2020). valuable information for the rapid development of COVID- 19 vaccine. As COVID-19 outbreak has triggered enormous critical challenges for the public health, research and medical Different stages of vaccine development: communities and serious economic loss that weigh heavily on the world order, it is urgent to understand the ongoing Even before starting clinical trials on humans, a test phase situation and to build strategies to contain the viral spread. known as the "preclinical studies" is necessary. In the first It is now evident that the best way to control and ultimately step, researchers work on cells and animals such as mice or end the pandemic is to develop a safe and effective vaccine monkeys to determine the immunogenicity of a new against coronavirus SARS-CoV-2. Currently, global vaccine. This step also makes it possible to verify the institutions and companies have started to develop vaccines safety of the vaccine formulation, either the optimal doses for the prevention of COVID-19. Here, we review the which make it possible to protect without causing current status of vaccine development for COVID-19. The undesirable effects, and finally the tolerance of the publication of the genetic sequence of SARS-CoV-2 on 11 subjects, or the side effects of the product. In these January 2020 (Wu et al. 2020), had elicited intense preclinical tests carried out on different animal species Research and development activity worldwide to develop a researchers use the same route of administration as that vaccine against the disease. which will be used in humans.

Once the preclinical tests have been successfully carried Under normal circumstances, the development of a vaccine out, the vaccine enters the stage of clinical trials, carried goes through several stages which can last up to 12 years out on humans, which comprises three phases. before its approval. This process requires years of research and testing before reaching the clinical stage, but the scale During phase 1, the product is administered to a small of the humanitarian and economic impact of the COVID- group of healthy people, between 10 to 100 volunteers. The 19 pandemic is driving evaluation of next-generation objective is then to ensure the safety of the vaccine in vaccine technology platforms through novel paradigms to injected subjects. accelerate development of a safe and effective coronavirus vaccine, and the first COVID-19 vaccine candidate entered In phase 2, hundreds of healthy volunteers are recruited to human clinical testing with unprecedented rapidity on 16 determine the efficacy of the vaccine, its ability to produce March 2020. As of December 17, 2020, more than 223 and also the amount of vaccine to be vaccine candidates are under active investigation, among administered for each subject. which 166 are in pre-clinical development and 57 in clinical development (WHO 2020b). These vaccines are A crucial phase 3 is finally carried out on a much larger developed using various technology platforms including 17 sample of people, around several thousand split into

106 Moroccan Journal Of Public Health Vol. 1, N° 1 (2020), 105-114 groups, such as children and the elderly. The vaccine is Vaccines can be divided into: administered to confirm its safety and effectiveness taking Live attenuated vaccines into account its side effects. This phase involve a control group which will receive a placebo. Live attenuated vaccines are derived from whole alive and functional disease-causing virus or bacteria which have Once a vaccine has been placed on the market, been weakened under laboratory conditions so it can pharmacovigilance activities make it possible to detect, replicate in the body for long time and elicited a strong and evaluate, understand, prevent and communicate any lasting protective immune response without causing the undesirable effects resulting from or any other disease in healthy people. Live attenuated microorganisms problem linked to the vaccine or vaccination. Long-term will grow in a vaccinated individual providing continual follow-up is often carried out in order to demonstrate that antigenic stimulation during sufficient time for memory the protection provided by the vaccine is safe and durable. cell production. Attenuated vaccines are mostly produced During a pandemic, researchers are often forced to speed passing the wild-type through a series of cell up vaccine development by combining phases. This is the cultures or animal embryos. With each passage, the case with coronavirus vaccines for which phases 1 and 2 pathogen loses its ability to replicate in human cells. are combined to test the vaccines directly on hundreds of Eventually, an attenuated virus will be unable to replicate people. If investigators observe worrying symptoms in the well (or at all) in human cells, and can be used in a volunteers, they can temporarily suspend a trial to take the vaccine. However, live vaccines are not suitable for people time to identify and mitigate the risks, and the development who have a compromised immune system response. process can resume or be abandoned. Administration of a live to these people may cause severe disease as a result of uncontrolled There are many approaches to vaccine development which replication of the vaccine virus. vary depending on the type of formulation. This difference affects how they are used, how they are administered and One concern to be considered is the possibility that the they are stored. Vaccines may be viral (live or inactivated), vaccine virus will revert to a wild type capable of causing , subunit (protein or polysaccharide) or nucleic disease due to that are frequently generated acid (DNA or RNA). Combination vaccines may include during replication of the viruses composing a live inactivated, protein-based and/or protein-conjugated attenuated vaccine. However, it is taken into consideration polysaccharide vaccine components. There has been an to limit the ability of the vaccine virus to replicate when increased focus on vaccine development using the viral- developing an attenuated vaccine. Protection against a live vector and nucleic-acid based platforms since the attenuated vaccine generally lasts longer than that provided appearance of the SARS-CoV-2 virus and COVID- by an . The protective immunity 19 disease in late 2019. Different vaccines can cause conferred by a live attenuated vaccine is generally stronger different side effects, and it is important to be familiar with and lasts longer than that provided by inactivated vaccine. these different types and know how to manage them to ensure their safety and effectiveness and to take into Inactivated vaccines account their suitability for all sections of the population, One alternative to attenuated vaccines are inactivated especially pregnant women and immunocompromised vaccines produced by inactivating a pathogen, using heat recipients. or chemicals such as formaldehyde or formalin. This

107 Moroccan Journal Of Public Health Vol. 1, N° 1 (2020), 105-114 destroys the pathogen’s ability to replicate, but keeps it Protein-based subunit vaccines “intact” so that the immune system can still recognize it. Protein-based subunit vaccines may be obtained by Because inactivated can’t replicate at all, they isolating a specific protein from a pathogen or produced112 can’t revert to a more virulent form capable of causing via genetic engineering. A gene coding for a vaccine disease as live attenuated vaccines. However, they tend to protein is inserted into genetic material of producer cells in provide a shorter length of protection than live vaccines, culture. When the carrier producer cell grows, the vaccine and are more likely to require adjuvants to generate strong protein is also produced. The immune system will and lasting immune response. recognize the expressed protein and provide future Unlike live attenuated vaccines, the administration of protection against the target virus (Bill 2015, Alexandra et inactivated vaccines to people with impaired immune al. 2019, Bellini et al. 2020). Unlike vaccines based on the system response does not carry any potential risk; however, whole pathogen, subunit vaccines include only a person with an impaired immune system response may components, or antigens, that best stimulate the immune not develop the same level of protection after vaccination system. While this technology can make vaccines safer, as a healthy person receiving the vaccine (Goossen et al. cheaper, easier to produce and more stable than those 2009, Bat et al. 2010, Meerveld-Eggink et al. 2011, containing whole viruses or bacteria, of protein Altamirano-Diaz et al. 2011). Some inactivated vaccines subunits alone are not sufficient to induce adequate long- may also require repeated doses to strengthen and lengthen term immunity. These immunogens often requires the the immune response to the vaccine conferring protection incorporation of adjuvants to elicit a strong protective against disease (Duchini et al. 2001, Soesman et al. 2000). immune response (Steven et al. 2009, Dennis et al. 2009). The risk of side effects is also minimized by restricting the Subunit vaccines also called ‘acellular’ immune system’s access to the whole pathogen.

Subunit vaccines contain only components, or antigens, Polysaccharide Vaccines chosen as targets for their key role in neutralizing . Unlike whole vaccines, subunit vaccines are safer and Some bacteria, when infecting humans, are protected by a easier to produce. However, antigens alone are not polysaccharide capsule that allows them to evade the sufficiently immunogenic to induce long-term protective body's defense systems, especially in infants and young immunity, hence the need to often complex them with children (Barrett 1985, Bruyn et al. 1991). Polysaccharide adjuvants to generate a strong protective immune response vaccines trigger an immune response against molecules (Zhang et al. 2020b). The strength of the use of only present in the capsule of the pathogen. These molecules are essential antigens in the vaccine preparation is the small and their immunogenicity is often lower. They reduction of the risk of inducing side effects. induce only short-term immunity, lack of immune memory Subunit vaccines can be classified into protein-based and not effective in infants and young children under 18 to subunit vaccines, polysaccharide vaccines and conjugate 25 months. The association of polysaccharide antigens with subunit vaccines (WHO 2020c). protein antigens in conjugate form induces a higher and more durable response (Cadoz 1998, Moore et al.

2000).

108 Moroccan Journal Of Public Health Vol. 1, N° 1 (2020), 105-114 Conjugate subunit vaccines cells using a brief electrical pulse, RNA must be encapsulated into lipid nanoparticle and injected. Potential Conjugate subunit vaccines induce an immune response advantages of this approach include the stimulation of against molecules expressed on the pathogen’s capsule. broad long-term immune responses, excellent vaccine Compared to single polysaccharide vaccines, they are stability and relative ease of large-scale vaccine produced by a technological process that binds the manufacture. Like other vaccine types, nucleic acid-based polysaccharide to a carrier protein to increase its vaccines have proven to be safe and tolerable (Robinson immunogenicity when used as a vaccine and induce a long- 1999, Gurunathan et al. 2000, Kutzler et al. 2008, Ulmer et term protective response even in infants. Various protein al. 2012). Although none of nucleic acid based vaccines are carriers are used for conjugation, including diphtheria and currently licensed for human use, many such vaccines are tetanus . Conjugate subunit vaccines, can therefore currently in the research pipeline. The manufacturing prevent common bacterial infections for which classical process for DNA vaccines is well-established, allowing polysaccharide vaccines are either ineffective or provide experimental vaccines to be quickly developed to address only short-term protection (OBARO et al. 2002, Rino et al. emerging infectious diseases. Many candidate DNA 2019, Lindberg 1999). The advent of conjugate subunit vaccines are developed to address several viral disease vaccines heralded a new age for against threats during outbreaks, including SARS coronavirus diseases caused by encapsulated organisms. (SARS-CoV) in 2003, H5N1 avian influenza in 2005, H1N1 pandemic influenza in 2009, and Zika virus in 2016. Toxoid vaccines The time from selection of the viral genes to be included in Toxoid vaccines are based on the toxin produced by certain the vaccine to initiation of clinical studies in humans was bacteria as immunogen (tetanus or diphtheria). The toxin shortened from 20 months with SARS-CoV to slightly produced by the bacteria is responsible for the symptoms longer than three months with Zika virus. of the disease (Rinaldo et al. 1999, Dhillon et al. 2017) (et Vaccines based on messenger RNA also are being al. 2001, Penina et al. 2020). The protein-based toxin is developed. Recent technological advances have largely inactivated to produce an anatoxin and used as an antigen overcome issues with the instability of mRNA and the in the vaccine to elicit immunity. To increase the immune difficulty of delivering it into cells, and some mRNA response, the toxoid must bind to an adjuvant (Edel et al. vaccines have demonstrated encouraging early results. 2004).

Rather than delivering DNA or mRNA directly to cells, Nucleic Acid Vaccines some vaccines use a harmless virus or bacteria as a vector, Although they have been the subject of work for several or carrier, to introduce genetic material into cells. Several years, DNA/RNA based vaccination technologies have such recombinant vector vaccines are approved to protect never yet been authorized for use in humans. Only four animals from infectious diseases, including and DNA vaccines have received regulatory approvals for distemper. Many of these veterinary vaccines are based on commercial use in animals. The approach of nucleic acid a technology that uses weakened versions of a poxvirus to based vaccines involves introducing genetic material deliver the pathogen’s genetic material. encoding the target antigen into the body’s own cells that All of these vaccine forms are now involved in the frantic use its machinery to produce the antigens from target race to develop an effective and safe vaccine against genetic material. While DNA is fired directly in the Covid-19 including new technologies based on the use of

109 Moroccan Journal Of Public Health Vol. 1, N° 1 (2020), 105-114 mRNAs that have never been used in humans until now. (Beigel et al. 2018). Studies have suggested that long‐lived The majority of vaccine candidates currently in clinical plasma cells play a critical role in maintaining serum trials target the spike (S) protein and its variants as the antibody level (Zhao et al 2017). primary antigen. However, candidates that target other or multiple antigens are progressing, including candidates that The COVID-19 vaccine R&D landscape has developed at target N protein, attenuated vaccines, inactivated vaccines unprecedented scale and speed since viral genome and peptide vaccines. The multiplicity of vaccine sequencing. There are over 223 confirmed COVID-19 formulations used in the development of an effective candidate vaccine under development of which 57 have vaccine against Covid-19 is prompted by the desire to already entered clinical phase in humans and at least 18 produce a vaccine capable of inducing a potent and vaccines are in phase 3 clinical trials, the final phase of effective antibody response as well as long‐term protection. testing. Geographically, the United States dominates the market with a 20% share of COVID-19 vaccine The exact mechanism required to induce long‐lived plasma development activities worldwide, followed by China with cells, hence, long‐term antibody responses, is in fact a 8% and France with 6%. fundamental immunological question that is central to vaccine design in general and, yet, not well understood. Pfizer/BioNTech

Studies have shown that monoclonal antibodies isolated On November 18, Pfizer and the German biotechnology from the COVID‐19 patients can neutralize SARS‐CoV‐2 company BioNTech developed one of the candidate (Ju et al. 2020, Chen et al. 2020, Chi et al. 2020). vaccines, BNT162b2, and showed it was 95% effective in Moreover, the use of convalescent plasma from the in preventing Covid-19 and has passed its safety checks, COVID‐19 recovery patients as a treatment strategy has led with no severe side effects beyond fatigue which affected to positive outcome (Duan et al. 2020, Shen et al. 2020). 3.7 per cent of participants and it was 94 percent effective These results confirm that protective antibody response in older adults, who usually are more vulnerable to against SARS‐CoV‐2 can be elicited. Nevertheless, developing severe COVID-19 (Joseph 2020). This vaccine whether long‐lasting protective antibody response can be candidate consists in injecting nucleoside-modified elicited by vaccination remains elusive. Three previous messenger RNA (mRNA) which functions as a blueprint studies on vaccine development against other for the virus spike protein. Once administered, the vaccine coronaviruses have shown that vaccines against stimulates the human immune system to produce SARS‐CoV or MERS‐CoV using either inactivated virions antibodies against this protein and thus the virus. Any or plasmid DNA have been tested in healthy adult cohort at successful vaccine based on this technology would be the phase I clinical trials (Lin et al. 2007, Martin et al. 2008). first mRNA vaccine approved for human use. This vaccine Although the majority of the recipients were found to requires two doses taken 21 days apart. seroconvert and produce neutralizing antibody against 110Pfizer and its German partner BioNTech have submitted an MERS‐CoV, antibody levels were only maintained at high application to the US Food and Drug Administration level for around 30 weeks and dropped to the level of (FDA) for an emergency use authorization of their vaccine baseline 60 weeks after vaccination. Similar phenomenon against COVID-19. If FDA authorization does come in the was observed in patients recovered from MERS‐CoV first half of next December, Pfizer and BioNTech will "be infection, where neutralizing antibodies dropped to an undetectable level as early as 6 months post-infection

110 Moroccan Journal Of Public Health Vol. 1, N° 1 (2020), 105-114 ready to distribute the vaccine candidate in US within later. But in a second trial conducted in Brazil, in which hours. volunteers received two full doses one month apart, the effectiveness dropped to 62 percent. When averaged, the Moderna Therapeutics efficacy is 70 percent. The benefit of this vaccine is that it can be stored in normal refrigeration. AstraZeneca and After Pfizer, On November 16, another US drugmaker, Oxford University plan to apply to an “emergency use Moderna Inc, announced that preliminary data of its phase listing” from the World Health Organization, which would three study of its mRNA-1273 experimental vaccine shows set up their candidate for distribution in lower income 94.5 percent effective in preventing COVID-19, more than countries. Oxford and AstraZeneca expect to produce up to that of Pfizer, without any significant safety concerns three billion doses of the vaccine in 2021. (Mahase 2020). Like Pfizer, Moderna has not presented underlying data on how the vaccine produced these effects. Sputnik-V In a separate announcement, the company also said its vaccine can be safely stored on ice or in a normal Russia's Sputnik Vaccine developed by Gameleya National refrigerator for 30 days. Moderna intends to apply FDA for Center of and Microbiology has an emergency use authorization of their vaccine against also drawn widespread attention, after the Russian COVID-19. government approved it for general use on August 11 without completing Phase 3 trials. Sputnik V is based Like Pfizer, however, Moderna released only early data on similar viral vector technology to that used in from their trial. There’s more work to be done before the Oxford-AstraZeneca coronavirus vaccine candidate, they’ll know if the vaccine really is safe and effective. And which early results indicate may be up to 90 per cent even if Moderna’s vaccine gets the approval from the effective (Burki 2020). But a full comparison between the F.D.A., it will take months to reach widespread two vaccines will only be possible when all the data is distribution. released. According to preliminary results obtained on volunteers 42 days after the injection of the first dose, the AstraZeneca/Oxford University Russian vaccine candidate, Sputnik V, would be 95% The Oxford vaccine, developed with AstraZeneca vaccine effective after two doses according to Russian Ministry of is the third to produce efficacy results, following Health and the Russian Federation. Pfizer/BioNTech and Moderna whose vaccines were made with a different technology. Oxford’s candidate is a constructed by transferring the SARS-CoV- China is the second competitor in the vaccine race behind 2 spike protein into a weakened version of an adenovirus. the USA with 10 vaccine candidates of which four were in When this adenovirus is injected into humans, the hope is Phase 3 clinical trials, the final and most important step that the spike protein will trigger an immune response. before regulatory approval. The most advanced are Sinovac and Sinopharm. On November 23, Oxford andAstraZeneca announced interim results from two of its Sinovac phase three trials (Folegatti et al. 2020, Callaway 2020). One conducted in the United Kingdom showed the vaccine Sinovac Biotech, a private Chinese company, developed an was 90-percent effective in preventing COVID-19 when inactivated vaccine called CoronaVac, one of four Chinese given as a half dose followed by a full dose one month vaccines in last-stage human trials. In June the company

111 Moroccan Journal Of Public Health Vol. 1, N° 1 (2020), 105-114 announced that Phase 1/2 trials on 743 volunteers found no following month. In summer, although Sinopharm has yet severe adverse effects and produced an immune response. to release Phase 3 data on either vaccine to demonstrate Sinovac published the details of the trial in November in a that they are safe and effective, the Chinese government medical journal, showing a comparatively modest had authorized Sinopharm vaccine inoculation to production of antibodies (Palacios et al. 2020). Only a government officials, health workers and other selected Phase 3 trial would demonstrate if that was enough to groups. As of November, nearly one million people in protect people from Covid-19. CoronaVac is capable of China had received the vaccines. In addition to their inducing a quick antibody response within four weeks of Wuhan vaccine, Sinopharm also began testing an immunization by giving two doses of the vaccine at a 14- inactivated virus vaccine developed by the Beijing Institute day interval. of Biological Products. After running early clinical trials in China, they launched Phase 3 trials in the United Arab In July, Sinovac launched a Phase 3 trial in Brazil, Emirates and Argentina. In October, the chairman of followed by others in Indonesia and Turkey. Although Sinopharm said the company was gearing up Sinovac has yet to release late-stage trial data, on October manufacturing for their two vaccines, with plans for 19, Brazilian officials said that CoronaVac was the safest producing a billion doses a year. of five vaccines they were testing in Phase 3 trials. The Chinese government gave the Sinovac vaccine emergency Conclusion approval for limited use in July. Meanwhile, Sinovac has been preparing to manufacture the vaccine for global Faced with the threat that SARS-CoV-2 represents on the distribution. The company planned on worldwide world population through its ability to cause repeated distribution of the vaccine in early 2021, including the epidemics and their consequences on mortality serious United States. economic disruptions and major upheavals in our style of life, rapid development of an efficacious vaccine against Sinopharm: SARS-CoV-2 is essential to avoid repeated or continuous outbreaks, but rigorous studies are required to determine The Wuhan Institute of Biological Products developed an the safety of candidate vaccines. It’s really important that inactivated virus vaccine, which the state-owned Chinese we pursue trials of many different vaccines from many company Sinopharm put into clinical tests. The Phase 1/2 different manufacturers and be able then to ensure the trial showed that the vaccine produced antibodies in supply of safe vaccine to the global population. Due to the volunteers, some of whom experienced fevers and other constraint to accelerating the vaccine development process, side effects. They launched Phase 3 trials in the United conclusions and decisions are often made on the basis of Arab Emirates in July and in Morocco and Peru the interim data from ongoing clinical and preclinical vaccine following month. The Wuhan Biologics Institute has studies. As a result, crucial information on longevity and developed an inactivated virus vaccine that has subjected to the quality of the protective immunity induced by the clinical testing by China's state-owned Sinopharm. The vaccine are not available. Finally, strong international phase 1/2 trial showed that the vaccine produced antibodies coordination and cooperation between vaccine developers, in volunteers, some of whom suffered from fever and other regulators, policymakers, funders, public health bodies and side effects. They launched phase 3 trials in the United governments will be needed to ensure that promising Arab Emirates in July and in Morocco and Peru the vaccine candidates can be manufactured in sufficient

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